3D chromatin remodeling potentiates transcriptional programs driving cell invasion.
CTCF
TAD
breast cancer
epigenetics
subTAD
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
06 09 2022
06 09 2022
Historique:
entrez:
29
8
2022
pubmed:
30
8
2022
medline:
1
9
2022
Statut:
ppublish
Résumé
The contribution of deregulated chromatin architecture, including topologically associated domains (TADs), to cancer progression remains ambiguous. CCCTC-binding factor (CTCF) is a central regulator of higher-order chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains unclear. We find that under physiological conditions, CTCF organizes subTADs to limit the expression of oncogenic pathways, including phosphatidylinositol 3-kinase (PI3K) and cell adhesion networks. Loss of a single CTCF allele potentiates cell invasion through compromised chromatin insulation and a reorganization of chromatin architecture and histone programming that facilitates de novo promoter-enhancer contacts. However, this change in the higher-order chromatin landscape leads to a vulnerability to inhibitors of mTOR. These data support a model whereby subTAD reorganization drives both modification of histones at de novo enhancer-promoter contacts and transcriptional up-regulation of oncogenic transcriptional networks.
Identifiants
pubmed: 36037342
doi: 10.1073/pnas.2203452119
pmc: PMC9457068
doi:
Substances chimiques
CCCTC-Binding Factor
0
Chromatin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2203452119Subventions
Organisme : CIHR
ID : 159759
Pays : Canada
Organisme : CIHR
ID : 159663
Pays : Canada
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